Introduction

β2-microglobulin (β2-M), the light chain of the class I major histocompatibility antigen, is a circulating protein that is impermeable to dialysis membranes. In the setting of renal failure, polymers of this protein accumulate and become amyloidogenic, possibly as a result of modification by advanced glycation end products. β2-M amyloidosis is a disabling complication of long-term hemodialysis or peritoneal dialysis with predominantly musculoskeletal manifestations. Patients present initially with shoulder pain, carpal tunnel syndrome, and flexor tenosynovitis of the hands. Less commonly, this type of amyloidosis may also present with visceral symptoms. Deposition of this amyloid protein in the blood vessels and interstitium of the gastrointestinal tract has been associated with abdominal pain, visceral perforation, pseudoobstruction, gastric and colonic dilatation, intestinal necrosis, malabsorption, and chronic diarrhea in patients on long-term hemodialysis. We report a patient with ischemic colitis related to β2-M amyloidosis and provide a summary of reported cases of gastrointestinal β2-M amyloidosis.

Case report

A 54-year-old African American man developed renal failure in 1980 as a result of chronic hypertension. He underwent hemodialysis until he received a cadaveric renal transplant in 1984. When the allograft was rejected in 1990, he resumed hemodialysis. In 1997, he developed shoulder pain and received steroid injections for presumed bursitis. He subsequently developed shoulder effusions, wrist pain, and hand paresthesias. Bilateral carpal tunnel syndrome was treated with surgical decompression. In March 1998, cystic lesions in the carpal bones of the right wrist were evident on radiographs and a clinical diagnosis of β2-M amyloidosis was established.

The patient was admitted to the hospital in November 2001 with diffuse abdominal pain that had begun insidiously 10 days prior to admission. He also reported that his chronic joint pain had worsened 2 months earlier, particularly in his shoulders, knees, ankles, and wrists. On physical examination, his blood pressure was 150/90 mm Hg. The abdomen was diffusely tender without rebound tenderness or guarding, bowel sounds were diminished, and there was no hepatosplenomegaly. There were flexion contractures of the fingers, decreased grip strength, limited motion of the wrists, bilateral shoulder effusions, and a large left knee effusion.

Hemoglobin was 10.0 gm/dl, white blood cell count was 11,300/mm3, and platelet count was 171,000/mm3. Creatinine was 12.4 mg/dl, bilirubin was 0.6 mg/dl, aspartate aminotransferase was 27 U/liter, and alanine aminotransferase was 15 U/liter. Amylase was 2,315 U/liter and lipase was 8,484 U/liter. On computed tomography of the abdomen, there was a small amount of fluid below the tail of the pancreas extending to the left renal fossa. The left knee synovial fluid white cell count was 8,700/mm3. With Congo red staining of the synovial fluid cell block, clumps of amyloid were evident in synovial tissue fragments. Serum β2-M level was 45 mg/liter (normal <1.7 mg/liter). Serum protein electrophoresis was normal.

The patient was managed conservatively for acute pancreatitis. Two weeks after admission, the patient developed profuse rectal bleeding and received 6 red blood cell transfusions. Six days later, his rectal bleeding recurred, prompting an emergency right hemicolectomy. On pathologic examination of the cecum and ascending colon, there was ischemic colitis with bleeding and ulceration. Amyloid infiltration was evident within the muscular walls of the small arteries and veins of the submucosa subjacent to the ulcerated mucosa (Figures 1 and 2). The amyloid deposits reacted immunohistochemically with antibodies directed to β2-M (Novocastra Laboratories, Newcastle upon Tyne, UK). Following hospital discharge, the patient was dialyzed using a high-flux rather than the standard Cuprophane low-flux membrane. His arthritis gradually improved.

Figure 2. Photomicrograph of resected colon showing Congo red–positive deposits in the wall of a submucosal vessel. The deposit is nodular and bulges into the vessel lumen. Congo red stain; original magnification × 40.

Discussion

β2-M amyloidosis is a relatively new disease whose incidence correlates directly with the increased lifespan of patients with end-stage renal disease maintained on hemodialysis. Clinical manifestations do not usually become evident until after 5 years of hemodialysis; their incidence rises progressively thereafter, reaching >80% in patients on hemodialysis for 15 years or more (1). Rheumatic manifestations predominate and include flexor tenosynovitis, carpal tunnel syndrome, destructive spondylarthropathy, and scapulohumeral arthropathy. Large periarticular osseous cysts predispose patients to pathologic fractures, especially in the hip.

Visceral deposits of β2-M amyloid are evident almost exclusively in patients who have been maintained on hemodialysis for >10 years (2, 3). Among such patients, the frequency of visceral deposition has been reported to range from 50% to 70% (2–4). The heart, stomach, and small bowel are most commonly involved (2, 5). Visceral deposition can be detected by rectal biopsy but not usually by abdominal fat aspiration (6). Echocardiography may support the diagnosis if the atrial septum is thickened and has increased echogenicity (4).

Visceral complications of β2-M amyloidosis are recognized infrequently. The case reports of 28 patients with gastrointestinal manifestations of β2-M amyloidosis are summarized in Table 1. Gastrointestinal manifestations of β2-M amyloidosis developed in these patients at a median of 14 years (range 6–24 years) after initiation of hemodialysis. The duration was ≥11 years in all but 2 patients. β2-M amyloid deposits were in the submucosal blood vessels and the interstitium of the bowel wall, particularly the muscularis propria. Vascular deposition was present in all cases. The most common gastrointestinal manifestations included bleeding (7 patients); dysmotility with pseudoobstruction, dilatation, and ileus (6 patients); and ischemia and infarction (5 patients). The site of amyloid deposition in the bowel did not correlate with the clinical manifestation.

Table 1. Summary of patients reported in the literature with gastrointestinal β2-M amyloidosis*

β2-M, AL (light chain), and AA (serum protein A) amyloid may each involve the gastrointestinal tract. Both β2-M and AL amyloid infiltrate the muscularis mucosae and muscularis propria; this is rarely seen in AA amyloidosis (5). All 3 types of amyloid are observed commonly in vessel walls. In β2-M amyloidosis, the vascular deposition is predominantly segmental and not circumferential as in AL or AA amyloidosis, resulting in subendothelial nodules that bulge into the vessel lumen (5). An example of this from our patient is shown in Figure 2. There is a reported increased presence of giant multinucleated cells in the areas with β2-M amyloid infiltration (7, 8).

In summary, patients with musculoskeletal manifestations of β2-M amyloidosis may develop gastrointestinal symptoms related to visceral amyloid deposition, particularly after 11 years of hemodialysis. Confirmation of the diagnosis is best achieved by biopsy of the bowel. Treatment of β2-M amyloidosis requires renal transplantation or hemodialysis with a high flux membrane.